Project Summary In the proposed research, we will test the scientific premise that single nucleotide variants in the p53 pathway will be risk factors for the etiology or pathogenesis of Iron Overload disorder in African Americans. This hypothesis is based upon our preliminary data on a mouse model for an African- specific variant in the p53 gene called Pro47Ser (hereafter S47). We find that S47 mice, compared to littermates with wild type p53, accumulate iron in their livers and show a marked predisposition to spontaneous liver cancer. This phenotype is markedly resemblant to Iron Overload disorder, which is an autosomal dominant disorder in African Americans of unknown genetic etiology, and which likewise shows iron accumulation and liver cancer predisposition. A preliminary study of 88 individuals from the HEIRs (Hemochromatosis and Iron Overload Screening Study) database, all of whom displayed signs of Iron Overload (high serum ferritin and high saturated transferrin) indicates that the allele frequency of S47 in this small subset is 5%, compared to 1.6% in unaffected African Americans. These combined preliminary data strongly support the premise that functionally significant genetic changes in the p53 pathway may underlie the cause, and exacerbate the pathology, of Iron Overload in African Americans. The long-term goal of this proposal is to analyze existent DNA/buffy coat samples from the HEIRs dataset of 479 African American individuals with signs of Iron Overload for the frequency of p53 pathway variants, with focus on three functionally- impactful variants: Pro47Ser, Pro72Arg, and SNP309 in the MDM2 gene. A natural corollary of this goal will be to search for associations between these variants and Iron Overload risk and severity of disease. Because Iron Overload is a chronic and devastating condition with no known cure that affects up to 2% of African Americans, defining the genetic basis of this disease in African Americans is a critical first step. The proposed research will thus address a critical unmet clinical need in this population.